1. Field of the Invention
The present invention provides novel mitomycin analogs containing a cyclic acetal or thioacetal group and to their use in the treatment of neoplastic disease states in animals. These compounds are mitomycin C analogs in which the 7-amino groups bears a 5-membered heterocyclic substituent. Mitomycin C is an antibiotic of established utility, and the 7-N-substituted mitosane analogs thereof have similar utility.
Nomenclature--The systematic Chemical Abstracts name for mitomycin A based on the recent revision [Shirhata et al., J. Am. Chem. Soc., 105, 7199 (1983)] is:
[1aS-(1a.beta.,8.beta.,8a-.alpha.,8b.beta.)]-8-[( (aminocarbonyl)oxy)methyl]-6,8a-dimethoxy-1,1a,2,8,8a,8b-hexahydro-5-methy l-arizino-[2',3' ,3,4] pyrrolo[1,2-a]indole-4,7-dione according to which the azirinopyrroloindole ring system is numbered as follows: ##STR1##
A trivial system of nomenclature which has found wide use in the mitomycin literature identifies the foregoing ring system including several of the characteristic substituents of the mitomycins as mitosane. ##STR2##
According to this system, mitomycin A is 7,9a-di-methoxymitosane and mitomycin C is 7-amino-9a-methoxy-mitosane. As to the stereochemical configuration of the products of this invention, it is intended when identifying them by the root name "mitosane" or by structural. formula to identify the stereochemical configuration thereof as the same as that of mitomycin C. The structures of Mitomycin A, B, C and of Porfiromycin are set out below: ##STR3##
2. Disclosure Statement
Mitomycin C is an antibiotic which is produced by fermentation and is presently on sale under Food and Drug Administration approval in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed (Mutamycin R Bristol Laboratories, Syracuse, N.Y. 13201, Physicians' Desk Reference 35th Edition, 1981, pp. 717 and 718). Mitomycin C and its production by fermentation is the subject of U.S. Pat. No. 3,660,578 patented May 2, 1972 claiming priority from earlier applications including an application filed in Japan on Apr. 6, 1957.
The structures of mitomycines A, B, C, and of porfiromycin were first published by J. S. Webb et al. of of Lederle Laboratories Division American Cyanamid Company, J. Am. Chem. Soc. 84, 3185-3187 (1962). One of the chemical transformations used in this structure study to relate mitomycin A and mitomycin C was the conversion of the former, 7-9.alpha.-dimethoxymitosane, by reaction with ammonia to the latter, 7-amino-9.alpha.-methoxymitosane. Displacement of the 7-methoxy group of mitomycin A has proven to be a reaction of considerable interest in the preparation of antitumor active derivatives of mitomycin C. The following articles and patents each deal inter alia with the conversion of mitomycin A to a 7-substituted amino mitomycin C derivative having antitumor activity. The object of this research was to prepare derivatives which were more active, and particularly which were less toxic than mitomycin C.
Matsui et al., J. Antibiotics, XXI, 189-198 (1968);
Konishita et al., J. Med. Chem., 14, 103-109 (1971);
Iyengar et al., J. Med. Chem., 24, 975-981 (1981);
Iyengar, Sami, Remers and Bradnet, Abstracts of Papers, 183rd Annual Meeting of the American Chemical Society, Las Vegas, Nev., March 1982, Abstract No. MEDI 72;
Iyengar et al., J. Med. Chem., 26, 16-20 (1983);
Iyengar et al., J. Med. Chem., 26, 1453-1457 (1983);
Cosulich et al., U.S. Pat. No. 3,332,944, issued Jul. 25, 1967;
Matsui et al., U.S. Pat. No. 3,420,846, issued Jan. 7, 1967;
Matsui et al., U.S. Pat. No. 3,450,705, issued Jun. 17, 1969;
Matsui et al., U.S. Pat. No. 3,514,452 issued May 26, 1970;
Nakano et al., U.S. Pat. No. 4,231,936, issued Nov. 4, 1980;
Remers, U.S. Pat. No. 4,268,676, issued May 19, 1981;
Remers, U.S. Pat. No. 4,460,599, issued Jul. 17, 1984;
Vyas et al., U.S. Pat. No. 4,487,769, issued Dec. 11, 1984.
Vyas et al., U.S. Pat. No. 4,567,256, issued Jan. 28, 1986;
Vyas et al., U.S. Pat. No. 4,579,737, issued Apr. 1, 1986;
Although there has been a considerable number of mitomycin C analogues prepared, none of the compounds of the present invention are disclosed in the references cited above or references cited therein.